DIPG & DMG (Diffuse Midline Glioma) Research & Clinical Trials

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BACKGROUND: Pediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer-related deaths. Those arising in the midline harboring a lysine to methionine substitution at position 27 in histone 3 (H3K27M), termed diffuse midline glioma (or DIPG when occurring in the pons), are particularly deadly and in need of additional therapeutic options. Our group and others have found upregulation of the RAS/MAPK pathway across HGGs, including DIPG; however, RAS is notoriously difficult to target therapeutically, with no approved drugs that can target nonmutant RAS proteins.

METHODS: We leveraged a pan-RAS-cleaving biologic (RRSP-DTB) to define RAS dependency in DIPG and employed proteomic profiling of patient-derived tumors to identify enriched cell-surface receptors for tumor-selective targeting. RRSP was re-engineered to engage the lead candidate receptor, tumor endothelial marker 8 (TEM8/ANTXR1), generating a targeted RAS-degrading biologic evaluated in vitro and in orthotopic DIPG xenograft models.

RESULTS: Pan-RAS cleavage revealed DIPG to be critically dependent on RAS/MAPK signaling compared to other RAS/MAPK HGGs. Targeting RRSP to TEM8 enabled efficient intracellular delivery, resulting in complete RAS ablation and apoptotic cell death in patient-derived DIPG cells at low picomolar concentrations. In vivo, intracerebroventricular delivery reduced leptomeningeal disease burden (P = .04), while convection-enhanced delivery extended survival in orthotopic DIPG models (median survival 68 vs. 57 days; P = .016).

CONCLUSIONS: We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.

BACKGROUND: Dordaviprone (ONC201) is the first FDA-approved therapy for H3K27M-mutant diffuse midline glioma (DMG). However, therapeutic response varies among patients, and no imaging biomarkers currently predict long-term benefit. Diffusion-weighted MRI and apparent diffusion coefficient (ADC) obtained during standard clinical imaging reflect tissue cellularity and necrosis, offering potential as an early response indicator.

METHODS: Clinical and imaging data from patients treated with dordaviprone (n = 83) on completed studies underwent centralized neuroradiology review, ADC histogram analysis, and functional diffusion mapping (fDM), which were compared and correlated to CSF tumor DNA (tDNA) and metabolomics when available. Final analysis included 38 patients receiving standardized dordaviprone dosing and treatment schedule.

RESULTS: In the pre-progression cohort, early changes in volumetric or cross-sectional RAPNO criteria were not predictive of overall (OS) or progression-free survival (PFS). Importantly, in patients treated pre-progression with dordaviprone post-radiation, tumors with increased diffusion ADC (reduced cellularity) at cycle 3 demonstrated median OS of 732 versus 360 days for those with decreased ADC (increased cellularity, P = .0149); with corresponding PFS of 334 versus 110 days (P = .0132). fDM analysis of spatio-temporal changes of ADC did not correlate with outcomes in a sub-cohort analysis but demonstrated predictive patterns in individual patient time course series. CSF metabolomics stratified by ADC change revealed differences in reductive stress metabolites among dordaviprone responders, linking ADC elevation to dordaviprone-driven metabolic effects.

CONCLUSION: Early increase in ADC correlates with improved response to dordaviprone in H3K27M-DMG and correlates with CSF metabolic changes, suggesting ADC warrants prospective validation as a biomarker.

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Cellular function relies on tightly regulated mitochondrial proteolysis, which controls organelle protein quality and specific mitochondrial functions, including gene expression and oxidative phosphorylation. In human mitochondria, one of the main proteolytic machineries is the soluble ClpXP complex, consisting of the protease ClpP and its chaperone ClpX, which degrades misfolded or aggregated proteins to preserve organelle function and integrity. As hyperactivation of ClpP has been shown to inhibit tumor cell growth in various types of cancer, this protease has become an important target for the development of small-molecule therapeutics. A piperazine-based compound, DA29, has proven effective in inducing cytotoxicity in diffuse intrinsic pontine glioma (DIPG) patient-derived cells and organoids, causing mitochondrial dysfunction and ROS accumulation. In this study, we employed in cellulo systems to conduct molecular and mechanistic analyses of ClpP hyperactivation mediated by DA29. Our data show that DA29 impairs mitochondrial function by specifically activating ClpP. Interestingly, degradation of ClpP itself is promoted when its proteolytic activity exceeds a certain threshold or is sustained for prolonged periods, suggesting a complex regulatory network that tunes protease levels within mitochondria.

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BACKGROUND: Diffuse midline glioma (DMG) with H3 K27 mutations are aggressive central nervous system tumors with limited treatment options and poor outcomes. Although more common in children, there is increasing recognition of adult cases, which remain under-characterized regarding longitudinal imaging trends and response to multimodal treatment. We aim to highlight heterogeneity and describe patterns of adult H3 K27-altered DMG in cases assessed at autopsy.

METHODS: Patients were included in the study if they were ≥ 21 years of age, and had a confirmed diagnosis of DMG, H3 K27-altered. Manual segmentations of contrast enhancement (CE) on T1-weighted post-contrast imaging and hyperintense FLAIR regions were performed at each timepoint. CE ratios (CE_vol/FLAIR_vol) were calculated to characterize enhancing versus infiltrative tumor burden. Treatment timelines were retrospectively aligned with imaging timing to evaluate disease progression and therapy response.

RESULTS: This case series included six patients with confirmed H3 K27-altered DMG. Longitudinal imaging data revealed radiographic heterogeneity between patients. Periods of FLAIR reduction were observed to occur around bevacizumab treatment. Mean CE ratios were lowest in Patients 5 and 1 (0.081 and 0.225 respectively), intermediate in Patient 4 (0.312), and highest in Patient 3 (0.668). ATRX-mutant cases (n, 2) had comparatively short overall survival of 26 and 164 days while ATRX-wild type cases (n, 4) survived 728-2,299 days.

CONCLUSIONS: Among our cohort, we observed two patients with ATRX mutations to have comparatively short survival periods. Findings highlight heterogeneity of adult H3 K27-altered DMG, and limitations of imaging-based modalities to track tumor progression.

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Read the abstract on PubMed ↗

Read the abstract on PubMed ↗

Read the abstract on PubMed ↗

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In multiple sclerosis (MS), new or enlarging brain lesions often suggest disease activity, but infections or tumors may mimic relapse. We report a 35-year-old woman with MS whose enlarging thalamic lesion was ultimately diagnosed as diffuse midline glioma, underscoring the need for prompt evaluation of atypical MRI findings.

BACKGROUND: Limited data exist regarding the safety and efficacy of photon re-irradiation with whole-brain radiotherapy (WBRT) or craniospinal irradiation (CSI) in children with recurrent or second primary CNS tumors.

MATERIALS AND METHODS: In this retrospective single-institution study, 23 patients < 21 years who underwent photon re-irradiation with WBRT (n = 9) or CSI (n = 14) for CNS tumors between 2013 and 2026 were included. Clinical and treatment characteristics were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Toxicities were graded using CTCAE v5.0.

RESULTS: In our cohort, the median age at diagnosis was 8.5 years (range: 0.2-19.7 years), and medulloblastoma was the most common histology (30%). Median time to the first relapse after initial irradiation was 12.0 months (range: 0.9-92.5 months). Median re-irradiation dose to the whole brain or craniospinal axis was 24.0 Gy (range: 20.0-36.0 Gy). For 15 patients who received involved field boosts, median total dose was 30.6 Gy (range: 20.0-54.0 Gy). With median follow-up after re-RT of 12.2 months (range: 1.0-106.8), 12-month PFS and OS were 24.2% and 67.0%, respectively. Four patients who received curative-intent re-CSI remain alive with median follow-up of 20.4 months (range: 5.8-106.8). The crude rate of grade >2 CNS toxicity was 8.7%. Of 10 patients with new neurologic symptoms before re-irradiation, 7 (70%) had symptomatic improvement after treatment.

CONCLUSIONS: Photon re-irradiation with WBRT or CSI was feasible and achieved disease control in a subset of patients and meaningful symptom palliation with acceptable acute toxicity. Careful attention to cumulative dose constraints is essential, and longer follow-up is needed to assess durability and late effects.

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Histone 3 lysine 27-to-methionine substitutions (H3K27M) drive aggressive diffuse midline gliomas by blocking differentiation of radial glial progenitor cells committed to oligodendrogenesis. We establish prolonged differentiation as a powerful tool to uncover regulators of glioma cell states and demonstrate that the pioneer transcription factor (TF) ASCL1 is a key mediator of H3K27M-driven plasticity and tumorigenesis. H3K27M prevents Polycomb silencing of ASCL1, co-opting this TF to maintain oligodendroglial progenitor states. Consistently, ASCL1 loss drastically impairs tumor formation in vivo. Mechanistically, ASCL1 synergizes with H3K27M to redistribute the chromatin remodeler BRG1 to regulatory elements co-enriched for ASCL1 and SOX motifs, promoting expression of stem and neural progenitor genes at the expense of mesenchymal genes in DMGs. ASCL1 loss acts as a "fire exit", enabling alternative differentiation despite H3K27M, underscoring the therapeutic potential of targeting stalled differentiation and tumor plasticity in histone-mutant gliomas and cancers with a stem cell hierarchy.

BACKGROUND: Gliomas diagnosed during pregnancy or postpartum pose diagnostic and management challenges. Neurologic symptoms may be attributed to physiological changes of pregnancy or the postpartum state, possibly delaying evaluation. When lesions arise in high-risk locations, such as the brainstem, tissue biopsy is frequently infeasible, further complicating the diagnostic process.

PATIENT PRESENTATION: A 28-year-old woman developed dysphagia during pregnancy, which persisted and gradually worsened after delivery. Postpartum evaluation identified a right thyroid nodule, subsequently diagnosed as papillary thyroid carcinoma following hemithyroidectomy. Eight months postpartum, the patient experienced progressive dysphagia, headaches, and dizziness. Magnetic resonance imaging revealed an expansile medullary lesion concerning for a high-grade primary brainstem tumor. Due to the brainstem location, biopsy was infeasible, and empiric chemoradiation was initiated for presumed high-grade glioma.

MOLECULAR FINDINGS: Cerebrospinal fluid (CSF) tumor-derived nucleic acid analysis using Summit 2.0 identified an H3-3A K28M alteration, along with co-occurring pathogenic alterations in NF1 and TP53. In conjunction with the clinical and radiographic findings, these molecular results supported classification of the tumor as diffuse midline glioma, H3 K27-altered.

MANAGEMENT AND OUTCOME: Following completion of chemoradiation, dordaviprone therapy was initiated. At the most recent documented follow-up in January 2026, brain MRI demonstrated decreased size and enhancement of the medullary lesion, accompanied by improvement in dysphagia, headaches, dystonic movements, balance, and overall performance status.

CONCLUSIONS: This case demonstrates that cerebrospinal fluid-based genomic profiling can provide clinically meaningful molecular information when tissue diagnosis is contraindicated and can inform treatment planning for patients with anatomically inaccessible central nervous system tumors. It also highlights the significance of ongoing evaluation of persistent neurologic symptoms during pregnancy and the postpartum period.

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Diffuse midline glioma (DMG) is a highly aggressive central nervous system neoplasm that predominantly affects pediatric populations and is associated with a dismal prognosis. Adult DMGs remain relatively uncommon and continue to pose significant diagnostic and therapeutic challenges. We present the case of a 54-year-old adult patient with a left thalamic DMG, H3 K27-altered, World Health Organization (WHO) grade 4, harboring pathogenic H3F3A K27M, KRAS G12V, and PHF6 mutations. The patient presented with headaches, fatigue, imbalance, dizziness, and slowed dexterity. Imaging demonstrated a heterogeneously enhancing left thalamic lesion extending into the midbrain, with associated edema and third-ventricular compression. Stereotactic biopsy confirmed a DMG, H3 K27-altered. Given the surgically inaccessible location and the high risk of neurologic morbidity, the patient underwent definitive radiotherapy without concurrent temozolomide. Follow-up imaging showed an interval reduction in tumor size, consistent with treatment response; however, a new subependymal ventricular nodule raised concern for possible early dissemination. This case highlights the importance of molecular characterization in adult DMG and discusses the potential biological implications of a KRAS comutation in this rare entity. We also review the evolving literature on adult thalamic DMG, molecular alterations, therapeutic considerations, and emerging targeted therapies, including dordaviprone (ONC201).